As more cancer patients display an extended survival brought about through the use of combined modality therapy, there is an increased concern with the effects of these therapeutic schedules on normal tissues. This project is designed to evaluate the effects of ionizing radiation and cancer chemotherapeutic agents, singly and in combination, on lung structure and function in Fischer 344 rats. We will study representative examples of various classes of cancer chemotherapeutic agents: alkylating agents, DNA-intercalating antibiotics, mitotic spindle poisons, and inhibitors of DNA-synthesis. We will determine to what extent these agents induce changes in the lung, and to what extent they potentiate the effects of a subsequent dose of radiation. In particular, we will investigate the induction of lung damage as a function of the time interval between treatments, and of the dose of radiation received. Secondly, we will monitor the latent period between the second treatment and the ultimate expression of damage. Physiological changes in lung function will be monitored using a lung plethysmograph and respirometer. Serum and tissue levels of angiotensin-1-converting enzyme will be monitored as a predictor of biochemical changes in lung function. At death, or after sacrifice, histological examination of various organs will be performed. Specifically the lung will be studied; however, heart and spinal cord will also be examined as to exclude death or lung changes due to damage expressed in these organs. The data will be correlated so as to assess changes in lung structure and function following combined modality treatment. The findings will serve as a guideline to predict and prevent long-term pulmonary deficit in patients treated for cancer with a combined modality approach that includes chemotherapy and subsequent radiotherapy.